4,6-Diaryl-pyrimidin-2(1H)-ones as sleep-inducers

ABSTRACT

The invention discloses compounds of the class of 1-substituted4,6-diaryl-pyrimidin-2(1H)-ones, e.g. 1-alkyl-4,6-diphenylpyrimidin-2(1H)-ones. The disclosure also includes the preparation of the pyrimidin-2(1H)-ones by oxidation of the corresponding dihydro derivatives and by cyclization of a dibenzoylmethane with an N-alkylurea. Utility as pharmaceutical agents such as tranquilizers, sleep-inducers and antiinflammatory agents is also disclosed.

United States Patent Hardtmann et al.

July 1, 1975 4,6-DIARYL-PYRIMIDIN-2( 1H )-ONES AS SLEEP-INDUCERSInventors: Goetz E. Hardtma nn, Florham Park;

Faizulla G. Kathawala, West Orange, both of NJ.

Assignee: Sandoz-Wander, Inc., E. Hanover,

Filed: Aug. 3, 1973 Appl. No.2 385,402

Related US. Application Data Division of Ser. No. 172,583, Aug. 17,1971, Pat. No. 3,772,272, which is a continuation-in-part of Ser. No.37,341, May 14, 1970, abandoned, which is a continuationin-part of Ser.No. 878,572, Nov. 20, 1969, abandoned.

US. Cl. 424/251 Int. Cl C07d 51/38 Field of Search 260/25 R; 424/251References Cited OTHER PUBLICATIONS Zagulyaeva et al., CA. 69, 77211b(1968).

Primary ExaminerDonald G. Daus Assistant Examiner-Raymond V. RushAttorney, Agent, or Firm-Gerald D. Sharkin; Richard E. Vila [5 7ABSTRACT 8 Claims, N0 Drawings 1 4,6-DIARYL-PYRIMIDIN-2-(ND-ONES ASSLEEP-INDUCERS This application is a division of copending applicationSer. No. 172,583, filed Aug. 17, 1971, now US. Pat. No. 3,772,272, whichin turn is a continuation-inpart of application Ser. No. 37,341, filedMay 14, 1970, which in turn is a continuation-in-part of applicationSer. No. 878,572, filed Nov. 20, 1969, now both abandoned.

The present invention relates to l-substituted-4,6-diaryl-pyrimidin-2(1l-l)-ones and to the preparation thereof. Theinvention also relates to compositions and methods for utilizingcompounds of said type and their pharmaceutical activities.

In accordance with the invention there is provided compounds of thegeneral formula I:

wherein R is lower alkyl of l to 5 carbon atoms, e.g. methyl,

ethyl and isopropyl,

each of R and R" is independently hydrogen, halo of atomic weight offrom 19 to 80, lower alkyl of l to 3 carbon atoms or lower alkoxy of 1to 3 carbon atoms,

R is hydrogen, halo of atomic weight of from 19 to 80, lower alkyl of 1to 3 carbon atoms, lower alkoxy of 1 to 3 carbon atoms, nitro ortrifluoromethyl,

each of R, and R is independently hydrogen, halo of atomic weight offrom 19 to 80, lower alkyl of 1 to 3 carbon atoms or lower alkoxy of 1to 3 carbon atoms, and

R is hydrogen, halo of atomic weight of from 19 to 80, lower alkyl of 1to 3 carbon atoms, lower alkoxy of 1 to 3 carbon atoms, nitro ortrifluoromethyl, provided generally that no more than one of R, R and R"and no more than one of R R and R is a branched chain hydrocarbon (alkyland alkoxy) substituent.

A Procedure A for preparing the compounds of formula I involves reactingan appropriately substituted or unsubstituted dibenzoylmethane of theformula II:

with a compound of formula Ill:

at elevated temperature to obtain a compound of the invention of formulaI:

wherein R", R, R, R, R R and R are as above defined. An alternateProcedure B for the preparation of the compounds of formula I involvessubjecting a compound of the formula IV to oxidation in an organicsolvent, said compound of formula IV being represented structurally asfollows:

in which R", R, R, R, R,, R and R are as defined.

The preparation of compounds I by Procedure A is conveniently carriedout in an organic solvent at elevated temperatures in the range of from50C. to 150C, preferably C. to C. and in the presence of an acid ascatalyst. The solvent employed is inert with respect to the reactantsand product and desirably a polar solvent of conventional type,preferably a lower carboxylic acid of 1 to 3 carbon atoms, morepreferably acetic acid. The catalyst employed may be any of severalsuitable strong acids including both inorganic and organic acids such ashydrogen chloride and p-toluenesulfonic acid, preferably hydrogenchloride. The reaction product of formula I may be isolated from 1ereaction mixture of Procedure A by working up by stablished procedures.In situations in which any subtituents on the 4-phenyl and 6-phenylmoieties are dif- :rent or differently placed it will be evident thatreacon product will be a mixture of the compounds of foriula I. Suchmixtures may be separated to recover the idividual products of formula Iby conventional proceures. I

The preparation of compounds I from compounds IV y the reaction ofProcedure B may be conveniently arried out in an inert organic solventat temperature 1 the range of C. to 150C. The oxidizing agents which maybe employed are of known type suitable for onverting an organic aminomoiety to an imino moity. Representative of such oxidizing agents arethe alali metal permanganates, such as sodium or potassium ermanganate,manganese dioxide and mercuric aceate, preferably manganese dioxide. Thepreferred temverature range when employing an alkali metal perianganateis 10-30C. and the preferred range when mploying manganese dioxide is80150C. The or- ,anic solvent may be any of several conventional or-,anic solvents including by way of illustration the aronatic solvents,e.g. benzene and the ethers including he cyclic ethers, e.g. dioxane.The reaction product of ormula I may be isolated from the Procedure Breacion by working up by established procedures.

The compounds of formulae II and III employed in rocedure A are eitherknown or may be prepared rom known materials by conventional procedures.

The compounds of formula IV are preferably preared in a two stepProcedure C involving reaction in I Step I a chalcone of the formula V:

ca ll HC Jvherein R, R, R", R R and R are as defined, with an alkylamineof the formula VI:

4 in an organic solvent to obtain said compound of formula IV.

The reaction Step 1 of Procedure C is desirably carried out attemperatures in the range of from minus 20C. to plus 35C., preferably inthe range of from plus 10C;, to 30C., with suitable provision being madewhen the compound of formula VI is a vaporous material at the reactiontemperature, e.g. by conducting the reaction under pressure. Thereaction may be carried out employing an excess of the compound VI assolvent medium for the reaction or any of several well knownconventional solvents may be suitably employed to provide a solventmedium. The reaction product of Step 1 is a compound of the formulaVIII:

NH n ",C

H vIII H C/ wherein R", R, R, R, R R and R are as defined, saidcompoundVIII being relatively unstable at higher temperatures and thereforedesirably maintained at lower temperatures below about 35C. for use inStep 2 of Procedure C.

In Step 2 of Procedure C the reaction product of Step l-is cyclized bysubjecting to reaction with isocyanic acid at temperature in the rangeof from minus 20C. to plus 35C., preferably in the range of from minus5C. to plus 15C. The isocyanic acid is known to be unstable and hence isdesirably formed in-situ by employing an isocyanate of the formulaVII-A:

wherein M is a metal cation displaced in an acidic medium to provide theisocyanic acid, said cation. M preferably being a cation of an alkalimetal, preferably sodium or potassium; or of an alkaline earth metal,e.g. calcium; or the cation of ammonium. The acid employed to producethe isocyanic acid in-situ is preferably acetic acid which may be alsoemployed as the organic solvent medium for reaction. The compounds offormula IV may be isolated from the Step 2 reaction mixture by workingup by established procedures.

The compounds of formulae V and VI employed as starting material inProcedure C are either known per se or may be prepared from knownmaterials by established procedures. I

The compounds of general formula I are useful because they possesspharmacological activity in animals. In particular, the compounds offormula I are useful as minor tranquilizers as indicated, for example,by exhib iting a depressant effect in behavior tests in mice and byadditionally exhibiting one or more responses from the group of anantagonism of amphetamine in mice, an inhibition of chemically inducedseizures in mice and a reinduction of hexobarbital anesthesia in mice.The compounds may also exhibit a CNS depressant effect in other animaltests, for example, by an inhibition of maximal electroshock inducedconvulsions in mice, by effecting a significant decrease of aggressionamong shock-induced mice and by effecting a loss of ability of mice toremain on a rotating rod. For such use the dosage of compound I will ofcourse vary depending upon known factors such as the particular compoundused and mode of administration. However, in general, satisfactoryresults may be obtained when administered at a daily dosage of from I to300 milligrams per kilograms of body weight, preferably given in divideddoses 2 to 4 times a day or in sustained release form. For most mammalsthe administration of from 60 to 2,000 milligrams of a compound offormula I per day provides satisfactory results and dosages formssuitable for internal administration comprise from about to 1,000milligrams of the compound in admixture with a solid or liquidpharmaceutical carrier or diluent.

Many of the compounds of the formula I are also useful asanti-inflammatory agents as indicated, for example, by the Carrageenaninduced edema test in rats on oral administration. Such activity ingeneral is exhibited by the compounds of formula I in which each of R,R, R", R R and R is hydrogen and also, for example, the specificcompounds of Examples 2 and 5d. For such use the dosage of compounds Iwill of course vary depending upon known factors such as the particularcompound used and mode of administration. However, in general,satisfactory results may be obtained when administered at a daily dosageof from 2 to 200 milligrams per kilograms of body weight, preferablygiven in divided doses 2 to 4 times a day or in sustained release form.For most mammals the administration of from 120 to 2,000 milligrams of acompound of formula l per day provides satisfactory results and dosageforms suitable for internal administration comprise from about 30 to1,000 milligrams of the compound in admixture with a solid or liquidpharmaceuticalcarrier or diluent.

In addition, the compounds of formula I are also useful assleep-inducers as indicated by sleep studies in cats having chronicallyimplanted electrodes. For such use of the compounds of formula I assleepinducers satisfactory results may be obtained in general onadministration at a dose of from 2 to 300 milligrams per kilograms ofbody weight. For most larger mammals the administration of a single doseof 120 to 2,000 milligrams of a compound of formula 1 providessatsifactory re sults and is typically administered at bedtime inadmixture with a solid or liquid pharmaceutical carrier or diluent. Aparticularly preferred sleepinducer of the formula l is the compoundl-ethyl-4,6-diphenylpyrimidin-2( ll-l)-one.

For the above uses, the pharmaceutically useful compounds provided bythe invention may be formulated in a conventional manner to contain aneffective dose of one or more of said compounds as active ingredienttogether with one or more conventional ingredients including an inertpharmaceutically acceptable carrier adapted to provide a compositionsuitable for either oral administration or for administrationparenterally in the form of an injectable solutionor suspension. In

" general, the preferred compositions are those adapted for oraladministration and conventional forms for this purpose are suitable,such as tablets, dispersible powders, granules, capsules, syrups,elixirs and the like. Such compositions for oral administration may beprepared according to any method known in the art for the manufacture ofpharmaceutical compositions, and such compositions may contain one ormore conventional adjuvants, such as sweetening agents, flavoringagents, coloring agents andpreserving agents, in order to provide anelegant and palatable preparation. Tablets may contain the activeingredient in admixture with conventional pharmaceutical excipients,e.g. inert diluents such as calcium carbonate, sodium carbonate, lactoseand talc, granulating and disintegrating agents, e.g. starch and alginicacid, binding agents,e.g. starch, gelatin and acacia, and lubricatingagents, e.g. magnesium stearate, stearic acid and tale. The tablets maybe uncoated or coated by known techniques to delay disintegration andadsorption in the gastro-intestinal tract and thereby provide asustained reaction over a longer period. Similarly, suspensions, syrupsand elixirs may contain the active ingredient in admixture with any ofthe conventional excipients utilized for the preparation of suchcompositions, e.g. suspending agents (methylcellulose, tragacanth andsodium alginate), wetting agents (lecithin, polyoxyethylene stearate andpolyoxyethylene sorbitan monooleate) and preservatives(ethyl-phydroxybenzoate). Capsules may contain the active ingredientalone or admixed with an inert solid diluent, e.g. calcium carbonate,calcium phosphate and kaolin. The preferred pharmaceutical compositionsfrom the standpoint of preparation and ease of administration are solidcompositions, particularly hard-filled capsules and tablets.

A representative formulation for oral administration at bedtime toinduce sleep is a tablet prepared by conventional tabletting techniquesand containing the following ingredients:

The following examples show representative compounds encompassed withinthe scope of this invention and the manner in which such compounds areprepared. However, it is to be understood that the examples are forpurposes of illustration only.

EXAMPLE 1 l-Methyl-4,6-diphenyl-pyrimidin-2( 1H )-one A solution of 15g. of dibenzoylmethane and 43.5 g. f M-methylurea in 250 m1. of glacialacetic acid is reluxed for 8 hours while dry hydrogen chloride gas isubbled through the reaction mixture. An additional mount of equivalentsof N-methylurea is then added nd refluxing continued for another 8 hourswhile bubling hydrogen chloride through the reaction system. heN-methylurea addition is again repeated and reluxing procedure continuedfor a further 8 hours. The l EXAMPLE 21-Methyl4,6-di(m-chlorophenyl)-pyrimidin- 2( lH)-one To a solution of 38g. di(m-chlorobenzoyl)methane l 400 ml. glacial acetic acid is added 23g. N- lethylurea and 57 g. p-toluene sulfonic acid. This mixlre isrefluxed for 24 hours and acetic acid removed y evaporation in vacuo.The residue is treated with N. sodium hydroxide till basic, extractedseveral times ith methylene chloride. The combined methylene ilorideextracts are then exhaustively extracted with ater, dried and evaporatedin vacuo to dryness. The :sidue is crystallized from methylenechloride/diethyl :her and then twice from benzene to obtain l-methyl-.6-di(m-chlorophenyl)-pyrimidine-2(lH)-one, m.p. 78-18lC.

EXAMPLE 3 Following the general procedure of the preceding Exnples 1 and2 the following compounds of the inven- 31'] are prepared:

1-ethy1-4,6-diphenyl-pyrimidin-2(lH)-one, 'm.p. l42l44C.(Crystallization from methylene chloride/diethyl ether). i

b. l-n-butyl-4,6-diphenyl-pyrimidin-2(lH)-one, m.p 123125C.(Crystallization from methylene chlori de/diethyl ether).

. l-ethyl-4,6-di(m-bromophenyl )-pyrimidin- 2(ll-l)-one, m.p. l44-146C.(Crystallization frorr methylene chloride/diethyl ether).

d. l-n-propyl-4,6-diphenyl-pyrimidin-2(1H)-one, m.p l69-172C.(Crystallization from methylene chloride/diethyl ether).

. 1-methyl-4,6-di( m-methylphenyl)-pyrimidin- 2(1H)-one, m.p. l5ll52C.(Crystallization frorr methylene chloride/diethyl ether).

EXAMPLE 4 l-Methyl-4-phenyl-6-( 3 ,4'-dimethoxy )phenylpyrimidin-2( ll-l)-one.

N ca 0 c=o 3 I 1r STEP A:

Preparation of l-methyl-4-phenyl-6-( 3 ,4 -dimethoxy )phenyl-3 ,4-dihydropyrimidin-2( 1H)-one A solution of 20 g. of 3,4-dimethoxychalconein a large excess methylamine is stirred at room temperature in a steelbomb overnight. The methylamine is then removed in vacuo at bathtemperature regulated below 25C. The oily residue is then dissolved withice bath cooling in 200 ml. of glacial acetic acid and to this solutionis added 5 equivalents of potassium cyanate. The reaction mixture isstirred at ice bath temperature 2 to 3 hours and then left overnightwith stirring at room temperature. Next day the reaction mixture isevaporated in vacuo, the residue treated with water and extracted withethyl acetate. The combined ethyl acetate extracts after washing withwater is dried over sodium sulfate and evaporated in vacuo. The residueis crystallized from methylene chloride/diethyl ether to obtainl-methyl-4-phenyl-6-( 3 ,4-dimethoxy)phenyl 3,4-dihydropyrimidin-2(lH)-one, m.p. l63l65C.

STEP B:

Preparation of lmethyl-4-phenyl-6-( 3 ,4'-dimethoxy)phenylpyrimidin-2(lH)-one A mixture of 6.0 g. of l-methyl-4-phenyl-6-(3,4-dimethoxy)phenyl-3,4-dihydropyrimidin-2( lH)-one, 6 g. of activatedmanganese dioxide and 250 ml. of xylene is refluxed for 48 hours, theresulting mixture filtered while hot and then cooled to obtain a solidmaterial which is collected and crystallized from methylenechloride/diethyl ether to obtain l-methyl-4-phenyl-6- 9 (3,4'-dimethyoxy)phenyl-pyrimidin-2(1l-l)-one, m.p. 2l7219C.

EXAMPLE Following the general procedure of Example 4 the 5 followingcompounds of the invention are prepared:

a. l-methyl-4-phenyl-6-( 3 ',4'-dichlorophenyl pyrimidin-2( lH)-one,m.p. 248-250C. (Crystallization from methylene chloride/diethyl ether).

b. 1-isopr0pyl-4,6-diphenyl-pyrimidin-2( ll-l)-one, m.p.

156-158C. (Crystallization from methylene chloride/diethyl ether).

c. 1-methyl-4-phenyl-6-(m-nitrophenyl )-pyrimidin- 2(1H)-one, m.p.22l223C. (Crystallization from methylene chloride/diethyl ether).

d. l-methyl-4-phenyl-6-(p-methyoxyphenyl pyrimidin-2( ll'l)-one, m.p.160-165C. (Crystallization from methylene chloride/diethyl ether).

. 1-methyl-4-phenyl-6-( 2',6 -dichlorophenyl)- pyrimidin-2(1l-l)-one,m.p. ether/petroleum l80-l82C. (Crystallization from diethylethre/petroleum ether).

f. l-ethyl-4-phenyl-6-( 3 ',4-dimethoxyphenyl pyrimidin-2(1H)-one, m.p.194-l96C. (Crystallization from methylene chloride/diethyl ether).

g. l-ethyl-4-( 3 ,44-dichlorophenyl )-6-phenylpyrimidin-2(1l-l)-one,m.p. 206-209C. (Crystallization from methylene chloride/diethyl ether).

h. 1-ethyl-4-(m-methoxyphenyl)-6-(m-nitrophenyl)- pyrimidin-2(1H)-one,m.p. 159-l61C. (Crystallization from methylene chloride/diethyl ether).

i. 1-ethyl-4-(m-nitrophenyl)-6-(mmethoxyphenyl)- pyrimidin-2(1H)-one,m.p. 206209C. (Crystallization from methylene chloride/diethyl ether).

What is claimed is:

l. The method of inducing sleep in a mammal comprising administering toa mammal a sleep-inducing effective amount of a compound of the formula:

wherein R is alkyl of 1 to 5 carbon atoms, each of R and R" isindependently hydrogen, fluoro,

chloro, bromo, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbonatoms,

R is hydrogen, fluoro, chloro, bromo, alkyl of 1 to 3 carbon atoms,alkoxy of l to 3 carbon atoms, nitro or trifluoromethyl,

each of R and R is independently hydrogen, fluoro,

chloro, bromo, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbonatoms, and

R is hydrogen, fluoro, chloro, bromo, alkyl of l to 3 carbon atoms,alkoxy of l to 3 carbon atoms, nitro or trifluoromethyl, provided thatno more than one of R, R and R" and no more than one of R R and R is abranched chain substituent.

2. The method of claim 1 in which each of R and R is hydrogen.

3. The method of claim 2 in which each of R and R is hydrogen.

4. The method of claim 2 in which each of R and R is hydrogen.

5. The method of claim 4 in which the compouund is1-ethyl-4,6-diphenyl-pyrimidin-2(1H)-one.

6. The method of claim 1 in which the compound is administered at a doseof from to 2000 milligrams.

7. A pharmaceutical composition comprising a solid pharmaceuticallyacceptable carrier and a sleepinducing effective amount of a compound ofthe formula:

wherein R is alkyl of l to 5 carbon atoms,

each of R and R is independently hydrogen, fluoro,

chloro, bromo, alkyl of l to 3 carbon atoms or alkoxy of 1 to 3 carbonatoms,

R is hydrogen, fluoro, bromo, chloro, alkyl of 1 to 3 carbon atoms,alkoxy of l to 3 carbon atoms, nitro or trifluoromethyl,

each of R, and R is independently hydrogen, fluoro,

chloro, bromo, alkyl of 1 to 3 carbon atoms or alkoxy of l to 3 carbomatoms, and

R is hydrogen, fluoro, chloro, bromo, alkyl of l to 3 carbon atoms,alkoxy of 1 to 3 carbon atoms, nitro or trifluormethyl, provided that nomore than one of R, R and R and no more than one of R,, R and R is abranched chain substituent.

8. A composition of claim 7 in which the compound is1-ethyl-4,6-diphenyl-pyrimidin-2( lH)-one.

1. THE METHOD OF INDUCING SLEEP IN A MAMMAL COMPRISING ADMINISTERING TOA MAMMAL A SLEEP-INDUCING EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA:2. The method of claim 1 in which each of R'''' and R3 is hydrogen. 3.The method of claim 2 in which each of R1 and R2 is hydrogen.
 4. Themethod of claim 2 in which each of R and R'' is hydrogen.
 5. The methodof claim 4 in which the compouund is1-ethyl-4,6-diphenyl-pyrimidin-2(1H)-one.
 6. The method of claim 1 inwhich the compound is administered at a dose of from 120 to 2000milligrams.
 7. A pharmaceutical composition comprising a solidpharmaceutically acceptable carrier and a sleep-inducing effectiveamount of a compound of the formula:
 8. A composition of claim 7 inwhich the compound is 1-ethyl-4, 6-diphenyl-pyrimidin-2(1H)-one.